Inhibition of human breast cancer cell proliferation by valproic Acid and melatonin

The anticonvulsant and oncostatic drug, valproic acid (VPA), upregulates melatonin MT1 receptor expression in rat C6 glioma cells. Since the MT1 receptor is involved in the oncostatic action of melatonin on human MCF‐7 breast cancer cells, the effect of VPA on its expression was examined. Treatment of MCF‐7 cells with VPA (0.5 or 1mM) for 24 or 72 h caused a significant increase in MT1 receptor expression, as shown by reverse transcription‐polymerase chain reaction analysis and western blotting. MTT [3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assays revealed a significant concentration‐dependent inhibition of MCF‐7 cell proliferation by VPA (0.5 – 5 mM), whereas melatonin (1 or 10 nM) was ineffective alone or in combination with VPA, in the first (MCF‐7A) subline examined. However, in subsequent experiments using a different (MCF‐7B) subline, which expressed significantly higher basal and VPA‐induced levels of the MT1 receptor, a combination of VPA and melatonin produced a marked synergistic inhibition of cell proliferation. These findings indicate that clinically relevant concentrations of VPA upregulate melatonin MT1 receptor expression in human breast cancer cells. Moreover, the enhanced antiproliferative effect observed with a combination of VPA and melatonin suggests that a similar therapeutic approach may be beneficial in human breast cancer. Supported by NSERC (Canada).